Project Summary Even though invasive lobular carcinoma (ILC) accounts for 10-15% of the breast cancer seen in the US, there remains much to be learned about the unique nature of this disease. For example, patients with ILC are likely to have tumors with expression of estrogen receptor alpha (ER), a biomarker of good prognosis. Yet, patients with ER+ ILC have worse long-term outcomes compared to patients with the more commonly studied subtype of ER+ invasive ductal carcinoma (IDC). The standard treatment regimen for ER+ disease includes endocrine therapy, so the big picture focus of this grant asks: why do some ILC patients have a worse outcome than expected on endocrine therapy, and for those patients, what additional treatments can we provide? This grant aims to assess the effect of FGFR4 expression on cell survival and signaling in vitro, identify biomarkers for FGFR4 activation in silico, and test the efficacy of FGFR4 inhibition on clinical samples ex vivo. Methods include 1) FGFR4 inhibition with shRNAs and small-molecule inhibitors, 2) RNA-Sequencing, 3) machine-learning, and 4) explant models of ILC patient tumors. The ultimate goal of the proposed aims is to provide rationale for specific combination targeted therapy in patients with lobular breast cancer, in accordance with the mission statement of the NCI.